Neurosciences Commons^™

Rare Heterozygous De Novo Variants In Rapgef2 Are Associated With A Neurodevelopmental Disorder, Ali H Bereshneh, Kirkland A Wilson, Xueyang Pan, Shabab B Hannan, Megan A Cooper, Jullianne Diaz, Eyby Leon, Tiana M Moses, Mahshid S Azamian, Daryl A Scott, Ping Yee Billie Au, Juan Pablo Appendino, Ingrid E Scheffer, Antony Kaspi, Melanie Bahlo, Michael S Hildebrand, Angela T Morgan, Ekanem Ekure, Joshua M Shulman, Friedhelm Hildebrandt, Jennifer E Posey, Paul Kruszka, Eric Vilain, Shinya Yamamoto, Oguz Kanca, Seth Berger, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Purpose: RAPGEF2 encodes a guanine nucleotide exchange factor (GEF) that activates small GTPases and has not been linked to a Mendelian disorder. RAPGEF2 is highly intolerant to loss-of-function variants. We report 5 de novo heterozygous variants in RAPGEF2 in unrelated individuals with developmental delay, attention deficit hyperactivity disorder, epilepsy, dysmorphic features, or other manifestations. We used a Drosophila model to assess the functional impact of the identified human variants.

Methods: We generated a Kozak-GAL4 null allele of the Drosophila ortholog of RAPGEF2, PDZ-GEF, and used the allele to determine the gene expression pattern as well as the loss-of-function phenotypes. We …

The Role Of Isotocin In Female Zebrafish (Danio Rerio) Reproductive Behavior And Its Implication For Intranasal Oxytocin Therapy In Humans, Katelynn M. Benge

Masters Theses

In the past several decades, oxytocin has been colloquially termed the “cuddle hormone,” due to its role in pair-bonding and monogamy (Carter et al., 1992). In addition to being used experimentally for psychological disorder, it has also been used in couple’s counseling settings (Anagnostou et al., 2014; Domes et al., 2016). The outcomes of this research reveal mixed results, creating a need for further research in the topic to understand the exact mechanisms by which oxytocin works in the brain to induce this prosocial response. This study sought to address this deficit through the zebrafish animal model. The zebrafish serves …

Task-Optimized Brain Parcellations Reveal Latent Functional Organization For Enhanced Connectivity-Based Neuroimaging Classification, Andrew Hannum, Mario A. Lopez

Computer Science: Faculty Scholarship

Brain parcellation schemes are fundamental to neuroimaging, yet general-purpose atlases may obscure the specific functional architecture relevant to a given cognitive task or clinical condition. This reflects a growing consensus that the “optimal” brain map is context-dependent. Here, we introduce a novel framework that validates this principle by generating task-optimized human brain parcellation maps directly from supervised learning objectives. Our method defines functional parcels by grouping brain regions based on the similarity of their contributions to a classifier's decision boundary for a specific goal (e.g., cognitive state decoding or clinical group separation). This approach prioritizes a region's discriminative role over …

Pathogenesis Of Polyglutamine Diseases: Piecing Together A Complex Molecular Puzzle, Esmeralda Villavicencio Gonzalez, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

Polyglutamine (polyQ) diseases, caused by a CAG repeat expansion encoding a glutamine tract in nine distinct proteins, present a complex molecular puzzle in which each piece contributes to neurodegeneration. While each of the causative proteins has a distinct function, the downstream consequences of polyQ toxicity are often similar, including protein accumulation, transcriptional dysregulation, somatic CAG repeat instability, disrupted energy homeostasis, compromised synaptic function, and selective neuronal death. This review summarizes emerging insights into how proteins with an expanded polyQ tract disrupt distinct cellular functions, and we examine a multitude of discoveries that are inspiring and reshaping novel therapeutic strategies.

Dark And Camouflaged Genomic Regions Remain Challenging In Chm13, Mark E. Wadsworth, Madeline L. Page, Bernardo Aguzzoli Heberle, Justin B. Miller, Cody J. Steely, Mark T. W. Ebbert

Sanders-Brown Center on Aging Faculty Publications

Comprehensive genomic analysis is essential for advancing our understanding of human genetics and disease. However, short-read sequencing technologies are inherently limited in their ability to resolve highly repetitive, structurally complex, and low-mappability genomic regions, previously coined as “dark” regions. Long-read sequencing technologies, such as PacBio and Oxford Nanopore Technologies (ONT), offer improved resolution of these regions, yet they are not perfect. With the advent of the new Telomere-to-Telomere (T2T) CHM13 reference genome, exploring its effect on dark regions is prudent. In this study, we systematically analyze dark regions across four human genome references—HG19, HG38 (with and without alternate contigs), and …

Data-Driven Thresholds For Standardized Classification Of Severe Alzheimer’S Disease Neuropathology Using Digital Neuropathology, Ryan K. Shahidehpour, Allison M. Neltner, Mitchell A. Klusty, Cole Corbett, Angelique D. Gonzalez, David A. Gutman, David W. Fardo, Adam D. Bachstetter, Cody Bumgardner, Margaret E. Flanagan, Peter T. Nelson

Sanders-Brown Center on Aging Faculty Publications

Alzheimer's disease neuropathological changes (ADNC)—operationalized with semi-quantitative parameters—represent the consensus-based gold standard for diagnostic evaluation of disease severity. Although useful, ADNC diagnostic frameworks have limitations, particularly in advanced disease stages where pathological severity varies widely within a given diagnostic category. Further, some individuals lacking cognitive impairment are inappropriately categorized as having severe ADNC. In this study, quantitative pathology metrics and alternative tissue sampling schemes were integrated with data about premortem cognitive status, in order to derive clinically informed neuropathologic diagnostic thresholds. Specific goals of the current study were to generate data-driven, standardized diagnostic cut-points, with the most severe stages of …

Clonal Expansion Of Cytotoxic Cd8⁺ T Cells In Lecanemab-Associated Aria, Lance A. Johnson, Kai Saito, Akhil V. Pallerla, Jessica L. Funnell, Ashley R. Ezzo, Chelsea M. Song, Douglas A. Harrison, Noah J. Norton, Lauren C. Moore, Linda J. Van Eldik, David W. Fardo, Greg E. Cooper, Josh M. Morganti

Sanders-Brown Center on Aging Faculty Publications

Amyloid-related imaging abnormalities (ARIA) are the principal safety concern limiting anti-amyloid therapies for Alzheimer’s disease, yet their biology remains unclear. Here we show, through multi-omic profiling of peripheral blood from three ARIA+ patients and matched controls, that ARIA is associated with coordinated reprogramming of CD8 + T cells. CD8+ effector memory (TEM) and terminally differentiated (TEMRA) subsets were expanded, clonally enriched, and transcriptionally primed for cytotoxicity and vascular trafficking. Transcription factor inference and metabolomics converged on glycolytic reprogramming favoring short-lived effector function. Ligand-receptor modeling revealed enhanced monocyte-to-T cell signaling through antigen presentation, adhesion, and chemokine axes, while integration with a …

From Fog To Function: An Occupational Therapist's Guide To Evaluating And Treating Cancer-Related Cognitive Impairments, Lauren E. Toner

Entry-Level Occupational Therapy Doctorate - Doctoral Capstone Symposium

Cancer – related cognitive impairment (CRCI) is a common side effect of cancer treatment that interferes with cancer survivors’ occupational performance, independence, and quality of life. Despite its high prevalence, CRCI remains under recognized and inconsistently addressed within oncology care. About 70% of individuals diagnosed with cancer report cognitive changes during or after treatment, yet many do not receive treatment. Occupational therapists are clinically trained to evaluate and treat functional cognition, activities of daily activities, instrumental activities of daily living, and client centered goals, positioning them as key providers in addressing CRCI. However, limited occupational therapy specific resources have hindered …

Nicotine Self-Administration And The Impacts On Medial Habenula And Interpeduncular Nucleus Neurophysiology, Nathan Alexander Olszewski

Theses, Dissertations and Capstones

Nicotine use is a tremendous public health issue in the United States, with over 23 million people being dependent on the substance. Low cessation rates associated with nicotine use are largely attributed to the withdrawal and craving symptoms that occur after abstinence of use from nicotine. The medial habenula (MHb) and interpeduncular nucleus (IPN) are two brain regions heavily associated and linked with nicotine withdrawal. Here, I sought to understand how these brain regions are altered in their physiology during nicotine intake. Utilizing E-Vape self-administration, mice were first taught to selfadminister nicotine of various, clinically relevant, dosages which correlate to …

Apoe4 Drives Maladaptive Heterogeneity And Immunometabolic Responses Of Astrocytes, Danielle S. Goulding, Holden C. Williams, Amy A. Gorman, Nicholas A. Devanney, Douglas A. Harrison, Adeline E. Walsh, Tony Tuck, Diana J. Zajac, Shannon L. Macauley, Steven Estus, Julia Tcw, Lance A. Johnson, Josh M. Morganti

Sanders-Brown Center on Aging Faculty Publications

Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimer’s disease (AD). Across the CNS, astrocytes are the predominant expressor of APOE while also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional inflammation and metabolic processes, yet insights into the molecular constituents driving these responses remain unclear. Utilizing complementary approaches across humanized APOE mice and isogenic human iPSC astrocytes, we demonstrate that ApoE4 alters the astrocyte immunometabolic response to pro-inflammatory stimuli. Our findings show that ApoE4-expressing astrocytes acquire distinct transcriptional repertoires at single-cell and spatially-resolved domains, which …

35 Individuals With Huwe1-Related Neurodevelopmental Disorder And Suggested Clinical Evaluations, Mindy H. Li, Deziree L. Coleman, Kelsey Hogan, Danielle Luz, Lindsay Bhandari, Newell Belnap, Tiffany Busa, Charles Coutton, Klaus Dieterich, Svetlana Gorokhova, Clara Hildebrandt, Rachel Logan, Milena Mariani, Manuela Morleo, Vincenzo Nigro, John Pappas, Rachel Rabin, Kelly Schoch, Angelo Selicorni, Vandana Shashi, Rebecca Spillman, Jennifer Sullivan, Charlotte Tardy, Samantha A. Schrier Vergano, Brock Grill, Kristin Baranano

Department of Pediatrics Faculty Publications

HUWE1 (HECT, UBA, and WWE Domain Containing E3 Ubiquitin Protein Ligase1, OMIM 300697), located at Xp11.22, encodes a ubiquitin ligase that is highly conserved across species. Genetic variants in HUWE1 described in multiple independent studies cause X-linked intellectual disability, including in the patients identified by Juberg, Marsidi, and Brooks. This report describes 35 additional cases of individuals with variants in HUWE1 and suggested guidelines for clinical management. Our study includes several female cases, which have not been widely reported previously. Our findings confirm earlier reported clinical features including developmental delay, autism, hypotonia, short stature, and dysmorphic facial features as well …

Neural Correlates Of Cognitive Fatigue In Regular Cannabis Users And Non-Users: A Pilot Fnirs Study, Mariia Vistyzenko

Theses and Dissertations (Comprehensive)

Background: Cognitive fatigue impairs performance across multiple domains, yet how regular cannabis use affects fatigue responses remains unclear. This pilot study investigated neural and behavioural correlates of cognitive fatigue in abstinent cannabis users versus non-users.

Methods: Twenty-six participants (18 non-users, 8 regular cannabis users after 24-hour abstinence) completed cognitive tasks before and after a 60-minute Sustained Attention to Response Task (SART) designed to induce fatigue. Tasks assessed working memory (N-Back), cognitive flexibility (Wisconsin Card Sorting), psychomotor speed (Digit Symbol Substitution), sustained attention (Continuous Performance Task), inhibition (Stroop, Stop Signal), and motion perception. Functional near-infrared spectroscopy (fNIRS) continuously monitored prefrontal cortex …

The Effects Of Stress-Related Hormones On Excitatory Synapse Formation, Autumn C. Garvey

Honors Undergraduate Theses

Stress profoundly influences brain function through neuromodulatory hormones that regulate synaptic plasticity, yet how temporal patterns of hormone exposure shape excitatory synapse formation remains poorly understood. This study investigates how exposure to stress hormones, norepinephrine and cortisol, affects excitatory synapse development. While existing research primarily compares concentration models, real-world stress occurs in variable patterns that may produce distinct neural outcomes. To address this gap, differentiated Neuro2A neuronal cells are exposed to norepinephrine or cortisol under a continuous treatment paradigm designed to model chronic stress conditions. Following treatment, immunofluorescence imaging is utilized to quantify excitatory synapse formation through analysis of presynaptic …

Dual Orexin Receptor Antagonism With Lemborexant Enhances Microglial Clearance Of Β-Amyloid In Mice, Ashish Sharma, Emiko Segawa, Xiaoying Chen, Sohui Park, Shoutang Wang, Riley E. Irmen, Nicholas J. Constantino, Chanung Wang, Michael F. Kanan, Marco Colonna, Shannon L. Macauley, Jocelyn Y. Cheng, Ken Hatanaka, Margaret Moline, Erik S. Musiek

Sanders-Brown Center on Aging Faculty Publications

Background: Sleep disturbances elevate brain amyloid-beta (Aβ) levels and represent a modifiable risk factor for Alzheimer’s disease (AD). The orexin/hypocretin system regulates sleep–wake behavior and has emerged as a therapeutic target in AD; however, the effects of FDA-approved dual orexin receptor antagonists (DORAs) on amyloid pathology remain unclear. We compared lemborexant, an FDA-approved DORA, to doxepin, an antihistaminergic sleep medication, on amyloid pathology and microglial responses in PSAPP mice.

Methods: PSAPP mice received lemborexant (10 or 30 mg/kg/day), doxepin (35 mg/kg/day), or vehicle for 6 weeks beginning prior to plaque onset or 4 weeks after established pathology. Sleep was assessed …

Age-Related Ultrastructural Differences In The Dorsal Cortex Of The Inferior Colliculus In The Fischer Brown Norway Rat, Kylee M. Tenney, Dakota Smallridge, Gillian Barach, Gurveer Singh, Erin Beskitt, Justine Busby, Syllissa Duncan, Alexa Wawrzyniak, Brenda Vega, Nick Tokar, Andrew Ohl, Jesse Young, Jeffrey Mellott

Williams Honors College, Honors Research Projects

The inferior colliculus is a nucleus in the auditory midbrain that plays an important role in sound and speech processing through how it encodes temporal precision. Temporal precision depends on the balance of inhibition and excitation within the IC. This balance degrades during aging. Age-related changes in synapses have been described in the lemniscal IC as a contributing factor for this imbalance. However, it is unknown if aging affects synapses throughout the non-lemniscal IC in a similar manner. We sought to determine this by examining the dorsal cortex of the IC. The ICd is a non-lemniscal nucleus that is well …

The Role Of P2y1 And P2y2 Receptors In Human Neural Stem Cell Proliferation, Daria Sokolova

Honors Undergraduate Theses

Endogenous neural stem cells (NSCs) are located in specialized niches of the adult brain and play a vital role in both neurogenesis and neuronal repair. However, declines in NSC proliferation and metabolism associated with age and pathology make these cells less efficient at responding to neurodegenerative disease. Understanding signaling pathways that regulate NSC function is therefore essential for the understanding and development of treatments for these conditions. P2Y receptors are G-protein-coupled purinergic receptors that are activated by extracellular nucleotides and regulate cellular metabolism and proliferation. Among the eight known P2Y subtypes, P2Y1 and P2Y2 have been linked to neuronal signaling …

Exploring Anticholinergic Neurotoxicity: Diphenhydramine's Impact On Neuro-2a Cell Morphology, Expression, And Viability, Jordan B. Mcintyre

Honors Undergraduate Theses

Anticholinergic medications, such as diphenhydramine (commonly known as Benadryl), are increasingly recognized for their association with cognitive impairment and neurodegenerative disease. These medications, which inhibit the action of acetylcholine, a neurotransmitter essential for the formation and utilization of the central and peripheral nervous system, have been implicated in conditions such as dementia and may impact fundamental cellular processes like neurogenesis and cell proliferation. This study investigates the effects of diphenhydramine on neurogenesis when introduced to Neuro-2a cells during differentiation. For all studies cells were plated on coverslips or in 6-well plates with differentiation media containing 0 ng/mL, 50 ng/mL, …

Family Mental Health – A Case Report, Vikrant Arora, Medha Kosireddy, Mathumitha Ananth, Kishor M. Manohar Rao

Digital Journal of Clinical Medicine

Psychiatric illness in India is estimated to be 15% as per National Mental Health Survey 2015-16.  Mental health challenges within families, especially depression, anxiety disorders that are not common and when unaddressed exert cascading effects on all members, disrupting emotional cohesion, relational functioning, and socioeconomic stability. There are few case reports on entire family presenting to psychiatry department.

With informed consent a city-based middle-class family of non-consanguineous origin, where the 40-year-old female, presented with intractable limb pains and health anxiety, she had multiple consultation in last few months and her 48-year-old husband also had with episodic pains, irritability and her …

Sox11 Overexpression Restores Embryonic Pro-Growth Transcription In Mature Corticospinal Tract Neurons, Eliazbeth Batsel, Zimei Wang, Elizabeth Otten, Syed Roshan, Rabia Mohammad, Paula Pascual, Darby O'Shea, Jose Rosas, Pantelis Tsoulfas, Murray G. Blackmore

Biomedical Sciences Faculty Research and Publications

Neurons in the central nervous system (CNS) display a high capacity for axon growth during early development but lose this ability at a pivotal differentiation stage marked by synaptic maturation, circuit integration, and a profound shift in gene transcription. Once mature, most CNS neurons fail to reverse this transcriptional switch after axon injury, fundamentally constraining their intrinsic capacity for axon regeneration. Here, we show with single-nucleus RNA sequencing that forced expression of the transcription factor Sox11 in mature corticospinal tract (CST) neurons produces large-scale and stable changes in gene expression that are highly enriched for growth-relevant processes, and which strongly …

The Postsynaptic Scaffolding Protein Sapap3 Shapes Mitochondrial Activity: The Case Of Huntington's Disease, Patrícia Coelho, Ildete Luísa Ferreira, Ana Sofia Lourenço, Daniela Marinho, Sandra Isabel Anjo, Zongwei Fang, Lígia Fão, Sandra I. Mota, Philippe J. Mas, Mário Carvalho, Rui Jorge Nobre, Carina Henriques, Joana Fraga, Dongqing Wang, Sandra Macedo Ribeiro, Luís Pereira De Almeida, Patrícia Monteiro, Isaura Simões, Darren J. Hart, Bruno Manadas, João Peça, Pedro Castanheira, A. Cristina Rego

Biological Sciences Faculty Publications

Postsynaptic scaffolding protein SAP90/PSD95-associated protein 3 (SAPAP3) modulates cortico-striatal signalling and regulates the maintenance of synaptic structure. Notably, SAPAP3 defects have been reported in several human psychiatric disorders that share pathophysiological features with Huntington’s disease (HD), a neurodegenerative disorder characterized by the expression of mutant huntingtin (mHTT) and marked dysfunction of cortico-striatal synapses and mitochondria. However, the role of SAPAP3 in mitochondrial function and HD pathophysiology remains unexplored. SAPAP3 was extracted from striatal synaptoneurosomes and analyzed by SWATH-MS proteomics to identify potential interactors, revealing SAPAP3 association with several mitochondrial proteins, particularly Mic60. These data were further complemented with proximity ligation …

Educational Attainment And Symptom Improvement In Treatment-Resistant Depression: A Longitudinal Cohort Analysis Across Treatment Modalities, Marjorie Harrison, Giselli Scaini Msc, Phd, Aspen Viamontes

Summer Research Program Abstracts

No abstract provided.

Neurodevelopmental Outcomes After Posthemorrhagic Hydrocephalus Of Prematurity, Mekal S. Mathew, Rene Leal, Caroline L. Hanan, David J. Sun, Hasan K. Mubarak, Amelie D. Perrier, William E. Johnson, Micolette R. Mardik, Trevor R. Alwell, Christian Amezquita Contreras, Chance E. Hatfield, Peter H. Yang

Summer Research Program Abstracts

No abstract provided.

Noradrenergic Innervation Across Brain Regions Is Altered By Aging And By Disease Progression In A Mouse Model Of Alzheimer’S Disease Neuropathology, Nicole M Hernandez, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

Norepinephrine plays critical roles in modulating arousal and attention, is highly dynamic in awake, behaving individuals, and has anti-inflammatory and neuroprotective actions. Notably, the locus coeruleus (LC), the primary source of norepinephrine in the central nervous system, is among the first brain regions to show pathological alterations in early stages of Alzheimer's disease (AD). LC neuronal loss and associated reductions in norepinephrine in the brain have therefore been postulated to play a key role in AD pathophysiology. LC neurons and their axons have been studied in several mouse models of AD-related neuropathology to investigate their contribution to brain dysfunction in …

A Balancing Act: Amyloid-Β, Tau, And Excitation-Inhibition In Alzheimer's Disease, Manuel Silva-Pérez, Jeannie Chin

Faculty, Staff and Students Publications

A growing body of evidence shows that epileptic activity is frequently observed in patients with Alzheimer's disease (AD), implicating underlying excitatory–inhibitory imbalance. The distinction of whether the AD-epileptic phenotype represents a subset of patients or an underdiagnosed manifestation holds major therapeutic implications. Here, we quantified the excitatory–inhibitory imbalance in AD patients using magnetoencephalography and examined the relationships to AD pathophysiology—amyloid-beta and tau, and to epileptic activity. We used two metrics to quantify regional excitatory–inhibitory imbalance distinguishing between local hyperexcitability (Neural excitability, quantified by regional aperiodic spectral slope) and aberrant long-range synaptic input integration (Neural fragility, quantified by …

Age-Related Variations Of The Hemodynamic Response Function Spatially Resolved Across Human Cerebral Cortex, Nooshin J Fesharaki, Amanda Taylor, David Ress

Faculty, Staff and Students Publications

Normal aging leads to regional vascular and neural alterations. Age-related impairments in neurovascular coupling (NVC) affect the blood-oxygen-level-dependent (BOLD) hemodynamic response function (HRF) measured with functional magnetic resonance imaging, causing changes in both amplitude and temporal dynamics. Previously, global, systematic age-related changes in HRF characteristics were demonstrated, consistent with known microvascular aging effects. In this follow-up study, a standard space was used to compare spatially resolved cortical HRF dynamics between sex-balanced groups of young and older adults. The results showed substantial age-related differences in both HRF amplitude and timing across distinct cortical regions. Nearly twice as much cortical area exhibited …

Refining Aicardi Syndrome Diagnostic Criteria: An Expert-Based Consensus Using A Modified Delphi Approach, Silvia Masnada, Valentina De Giorgis, Umberto Carugo, Nadia Bahi-Buisson, Mara Cavallin, Mark Corbett, Manuela Formica, Jozef Gecz, Natalia Petros, Emilio Perucca, Anna Pichiecchio, Paolo Fusar Poli, Elliott H Sherr, Ignatia B Van Den Veyver, Federico Zara, Martin Geroldinger, Pierangelo Veggiotti, Alexis Arzimanoglou

Duncan NRI Faculty and Staff Publications

Background and objectives: Aicardi syndrome (AIC) is a rare neurodevelopmental disorder historically characterised by the presence of chorioretinal lacunae, corpus callosum agenesis, infantile spasms and several supporting features that aid in diagnosis. However, the unclear aetiology and evolving diagnostic tools have led to ongoing reconsideration of the criteria, based on individual approaches. Our study aimed to establish, for the first time, an expert-based consensus on diagnostic criteria for AIC by integrating both existing and novel ones.

Methods: A geographically diverse and multidisciplinary group of expert physicians was invited to participate in a modified Delphi study, to achieve consensus on major, …

Telethon Undiagnosed Disease Program: Structured Approach To Solving Rare Childhood-Onset Genetic Diseases, Annalaura Torella, Manuela Morleo, Carmine Spampanato, Raffaele Castello, Mariateresa Zanobio, Giulio Piluso, Pasquale Di Letto, Maria Elena Onore, Sarah Iffat Rahman, Francesco Musacchia, Michele Pinelli, Giuseppina Vitiello, Giulia De Riso, Angelo Selicorni, Milena Mariani, Cecilia Daolio, Valeria Capra, Marcello Scala, Francesca Nardecchia, Serena Galosi, Mario Mastrangelo, Filippo Manti, Donatella Milani, Corrado Romano, Donatella Greco, Claudia Ciaccio, Stefano D'Arrigo, Arianna De Laurentiis, Antonietta Coppola, Marcella Zollino, Domizia Pasquetti, Federica Francesca L'Erario, Albina Tummolo, Claudia Santoro, Livia Garavelli, Carla Marini, Stefania Bigoni, Alfonsina Tirozzi, Viviana Cetrangolo, Giancarlo Parenti, Diego Di Bernardo, Angela Peron, Silvia Maitz, Andrea Accogli, Gerarda Cappuccio, Sandro Banfi, Giorgio Casari, Andrea Ballabio, Nicola Brunetti-Pierri, Vincenzo Nigro, Telethon Undiagnosed Disease Study Group

Duncan NRI Faculty and Staff Publications

Purpose: Many children with severe genetic disorders remain undiagnosed despite advanced genomic technologies. Early diagnosis is vital for prognosis, genetic counseling, and targeted treatment development. This study aims to increase diagnostic rates in complex pediatric cases and foster research into disease mechanisms.

Methods: Launched in 2016, the Telethon Undiagnosed Diseases Program provides a structured, multicenter approach to rare disease diagnosis. Standardized case submission criteria ensured consistent clinical data collection. Children with severe, multisystemic disorders and prior negative genetic tests were eligible. After case approval, trio-based exome sequencing was performed, with regular reanalysis for unsolved cases until December 2024.

Results: Between …

Cerebellar Motor And Non-Motor Contributions To Dystonia Pathophysiology And Treatment, Linda H Kim, Cheryl Brandenburg, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Dystonia is a complex neurological disorder characterized by sustained or intermittent abnormal movements and/or postures. However, dystonia's non-motor symptoms, particularly the sleep disturbances, are critical yet underexplored concerns that affect all ages. Here, we synthesize current knowledge on the motor and non-motor domains of dystonia, emphasizing the functional interconnections and plasticity within cerebellar motor, cognitive, and sleep-associated circuits to motivate more comprehensive and effective treatments that improve overall quality of life.

Beta-Band Modulation Reveals The Cortical Dynamics Of Auditory Statistical Learning In Children, Jarrad A.G Lum, Christine N. Moreau, Li Ann Leow, Welber Marinovic, Sarah J. Lum, Marc F. Joanisse, Laura J. Batterink

Research outputs 2022 to 2026

Children's ability to extract statistical regularities from speech is considered fundamental to lexical, syntactic, and grammatical development. However, the neural oscillatory mechanisms supporting this process in childhood remains poorly understood. While beta-band oscillations have been linked to statistical learning in visual and motor domains, it is unclear whether similar dynamics support auditory statistical learning in children. In this study, we recorded electroencephalography (EEG) from children aged 8–12 years as they listened to a continuous stream of trisyllabic nonwords (e.g., dapiku), where syllable order within each nonword was fixed (high predictability), but transitions between nonwords were variable (low predictability). Beta power …

Insulin Resistance As A Mediator Of Physical Activity's Effects On Beta-Amyloid Accumulation And Tau Phosphorylation: A Scoping Review, Michael G. Slee, Joanne Scotney, Stephanie R. Rainey-Smith, Kirk I. Erickson, Hamid R. Sohrabi, Giuseppe Verdile, Belinda M. Brown

Research outputs 2022 to 2026

Background Type 2 diabetes is associated with increased Alzheimer’s disease risk and brain beta amyloid (Aβ) burden, suggesting an underlying mechanistic relationship between Alzheimer’s disease and type 2 diabetes. Animal studies show exercise reduces levels of brain Aβ and tau, and while human studies are somewhat limited, some studies have reported physical activity is associated with lower brain Aβ and tau levels. Exercise has well established links to reductions in insulin resistance; thus, as physical activity can impact both insulin resistance and Alzheimer’s disease pathology and/or biomarkers, it is reasonable to hypothesise that a mediating relationship may exist. The objective …